Semester-IV

Sub Name-medicinal chemistry-I (sub code-BP-402T)

Objective
Medicinal Chemistry
Introduction, History and development of medicinal chemistry.
Physicochemical properties in relation to biological action
Ionization, Solubility, Partition Coefficient, Hydrogen bonding, Protein binding,
Chelation, Bioisosterism , Optical and Geometrical isomerism.
Drug metabolism
Drug metabolism principles- Phase I and Phase II.
Factors affecting drug metabolism including stereo chemical aspects.

Introduction

Medicinal chemistry and pharmaceutical chemistry are disciplines at the intersection

of chemistry, especially synthetic organic chemistry, and pharmacology and various other
biological specialties, where they are involved with design, chemical synthesis and development
for market of pharmaceutical agents, or bio-active molecules (drugs).
Compounds used as medicines are most often organic compounds, which are often divided into
the broad classes of small organic molecules (e.g., atorvastatin, fluticasone, clopidogrel) and
"biologics" (infliximab, erythropoietin, insulin glargine), the latter of which are most often
medicinal preparations of proteins (natural and recombinant antibodies, hormones,
etc.). Inorganic and organometallic compounds are also useful as drugs
(e.g., lithium and platinum-based agents such as lithium carbonate and cisplatin as well
as gallium).
In particular, medicinal chemistry in its most common practice—focusing on small organic
molecules—encompasses synthetic organic chemistry and aspects of natural products
and computational chemistry in close combination with chemical
biology, enzymology and structural biology, together aiming at the discovery and development
of new therapeutic agents. Practically speaking, it involves chemical aspects of identification,
and then systematic, thorough synthetic alteration of new chemical entities to make them suitable
for therapeutic use. It includes synthetic and computational aspects of the study of existing drugs
and agents in development in relation to their bioactivities (biological activities and properties),
i.e., understanding their structure-activity relationships (SAR). Pharmaceutical chemistry is
focused on quality aspects of medicines and aims to assure fitness for purpose of medicinal
products.
At the biological interface, medicinal chemistry combines to form a set of highly
interdisciplinary sciences, setting its organic, physical, and computational emphases alongside
biological areas such as biochemistry, molecular
biology, pharmacognosy and pharmacology, toxicology and veterinary and human medicine;
these, with project management, statistics, and pharmaceutical business practices, systematically
oversee altering identified chemical agents such that after pharmaceutical formulation, they are
safe and efficacious, and therefore suitable for use in treatment of disease.

History
Medicinal chemistry's roots can be found in the fertile mix of ancient folk medicine and early
natural product cizemistn;, and hence its name. As appreciation for the links between chemical
structure and observed biological activity grew, medicinal chemistry began to emerge about 150
years ago as a distinct discipline intending to explore these relationships via chemical
modification and structural mimicry of nature's materials, )particularly with an eye toward
enhancing the efficacy of substances thought to be of therapeutic value.
Just as in all fields of science, the history of medicinal chemistry is comprised of the ideas,
knowledge, md available tools that have advanced contemnor knowledge. The spectacular
advances in medicinal chemistry over the years are no exception. Burger3 stated that" the great
advances of medicinal chemistry have been achieved by two types of investigators: those with
the genius of prophetic logic, who have opened a new field by interpreting correctly a few well-
placed experiments, whether they pertained to the design or the mechanism of action of drugs;
and those who have varied patiently the chemical structures of physiologically active compounds
until a useful drug could be evolved as a tool in medicine.
The nineteenth century age of innovation and chemistry the nineteenth century saw a great
expansion 111 the knowledge of chemistry, which greatly extended the herbal ph, llmacopeia
that had preViously been established. Building on the work of Lavoisier, chemists throughout
Europe refined and extended the techniques of chemical analysis. The synthesis of acetic acid by
Kolbe in 1845 and of methane by Berthelot in 1856 set the stage for organic chemically. The
emphasis was shifted from finding new medicaments from the vast world of plants to the finding
of active ingredients that accowlted for their pharmacologic properties. The isolation of
morphine by Sertiirner in 1803, of emetine from ipecacuanha by Pelletier in 1816, and his
purification of caffeine, quinine, and colchicines in 1820 all contributed to the increased use of
"pure" substances as therapeutic agents. The nineteenth century also contributed to the use of
digitalis by William Withering, the English physician and botanist, for the treatment of dropsy.
Niemen isolated cocaine in 1860 and the active ingredient, Physotigmine, from the Calabar bean
in 1864.
The twentieth century and the pharmaceutical industry Diseases of protozoal and spirochetes
origin responded to synthetic chemotherapeutic agents. Interest in synthetic chemicals that could
inhibit the rapid reproduction of pathogenic bacteria and enable the host organism to cope with
invasive bacteria was dramatically increased when Domagk reported that the red dyestuff 2,-!-
diaminoazobenzene-4' -sulfonamide (Prontosil) dramatically cured dangerous, systemic Cr,ll11-
positive bacterial infections in man and animals. The observation by Woods and Fildes in 1940
that the bacteriostatic action of sulfon,lmide-like drugs was antagonized by p-aminobenzoic acid,
was one of the early examples in which a balance of stimulatory and inhibitory properties
depended on the structural analogies of chemicals.

Drug Metabolism
The human body is an example of an exquisitely designed, extremely complex machine that
functions day-in and day-out to allow for survival of the organism in response to a never-ending
onslaught of external challenges. When one considers the enormous variety of environmental
stressors to which the body is continually subjected, it is not surprising to anticipate the existence
of a multitude of checks and balances associated with its physiological and biochemical systems.
Humans are exposed throughout their lifetime to a large variety of drugs and nonessential
exogenous (foreign) compolmds (collectively termed "xenobiotics") that may pose health
hazards. Most drugs and other xenobiotics are metabolized by enzymes normally associated with
the metabolism of endogenous constituents (e.g., steroids and biogenic amines). The liver is the
major site of drug metabolism, although other xenobiotic-metabolizing enzymes are fowl in
nervous tissue, kidney, lung, plasma, and the gastrointestinal tract. Among the more active extra
hepatic tissues capable of metabolizing drugs are the intestinal mucosa, kidney, and lung. The
ability of the liver and extra hepatic tissues to metabolize substances to either pharmacologically
inactive or bioactive metabolites before reaching systemic blood levels is termed" first-pass
metabolism.

Phase I reactions (Biotransformations)

This type includes oxidation, hydroxylation, reduction, and hydrolysis. In these enzymatic
reactions, a new functional group is introduced into the substrate molecule, an existing functional
group is modified, or a functional group or acceptor site for Phase II transfer reactions is
exposed, making the xenobiotic more polar and, therefore, more readily excreted.

Phase II reactions (Conjugation)

These reactions are enzymatic syntheses whereby a functional group, such as alcohol, phenol, or
amine, is masked by the addition of a new group, such as acetyl, sulfate, glucuronic acid, or
certain amino acids, which further increases the polarity of the drug or xenobiotic. Most
substances undergo both Phase I and Phase II reactions sequentially.

Physicochemical properties in relation to biological action

✓ Ionization
Ionization or ionisation is the process by which an atom or a molecule acquires a negative
or positive charge by gaining or losing electrons, often in conjunction with other
chemical changes. The resulting electrically charged atom or molecule is called an ion.
Ionization can result from the loss of an electron after collisions with subatomic particles,
collisions with other atoms, molecules and ions, or through the interaction
with electromagnetic radiation. Heterotypic bond cleavage and heterolysis substitution
reactions can result in the formation of ion pairs. Ionization can occur through radioactive
decay by the internal conversion process, in which an excited nucleus transfers its energy
to one of the inner-shell electrons causing it to be ejected.
 Production of ions
Negatively charged ions are produced when a free electron collides with an atom and is
subsequently trapped inside the electric potential barrier, releasing any excess energy. The
process is known as electron capture ionization.
Positively charged ions are produced by transferring an amount of energy to a bound electron in
a collision with charged particles (e.g. ions, electrons or positrons) or with photons. The
threshold amount of the required energy is known as ionization potential. The study of such
collisions is of fundamental importance with regard to the few-body problem, which is one of the
major unsolved problems in physics. Kinematic ally complete experiments,[1] i.e. experiments in
which the complete momentum vector of all collision fragments (the scattered projectile, the
recoiling target-ion, and the ejected electron) are determined, have contributed to major advances
in the theoretical understanding of the few-body problem in recent years.
Adiabatic ionization is a form of ionization in which an electron is removed from or added to
an atom or molecule in its lowest energy state to form an ion in its lowest energy state.
The Townsend discharge is a good example of the creation of positive ions and free electrons
due to ion impact. It is a cascade reaction involving electrons in a region with a sufficiently
high electric field in a gaseous medium that can be ionized, such as air. Following an original
ionization event, due to such as ionizing radiation, the positive ion drifts towards the cathode,
while the free electron drifts towards the anode of the device. If the electric field is strong
enough, the free electron gains sufficient energy to liberate a further electron when it next
collides with another molecule. The two free electrons then travel towards the anode and gain
sufficient energy from the electric field to cause impact ionization when the next collisions
occur; and so on. This is effectively a chain reaction of electron generation, and is dependent on
the free electrons gaining sufficient energy between collisions to sustain the avalanche.
Ionization efficiency is the ratio of the number of ions formed to the number of electrons or
photons used.
Types of ionization
There are many types of ionization methods are used in mass spectrometry methods. The classic
methods that most chemists are familiar with are electron impact (EI) and Fast Atom
Bombardment (FAB). These techniques are not used much with modern mass spectrometry
except EI for environmental work using GC-MS.
Solubility
Solubility is the property of a solid, liquid or gaseous chemical substance called solute to
dissolve in a solid, liquid or gaseous solvent. The solubility of a substance fundamentally
depends on the physical and chemical properties of the solute and solvent as well as on
temperature, pressure and presence of other chemicals (including changes to the pH) of the
solution. The extent of the solubility of a substance in a specific solvent is measured as the
saturation concentration, where adding more solute does not increase the concentration of the
solution and begins to precipitate the excess amount of solute.
Factors affecting solubility
Temperature
The solubility of a given solute in a given solvent typically depends on temperature. Depending
on the nature of the solute the solubility may increase or decrease with temperature. For most
solids and liquids, their solubility increases with temperature. In liquid water at high
temperatures, (e.g. that approaching the critical temperature), the solubility of ionic solutes tends
to decrease due to the change of properties and structure of liquid water; the lower dielectric
constant results in a less polar solvent.
Gaseous solutes exhibit more complex behavior with temperature. As the temperature is raised,
gases usually become less soluble in water (to minimum, which is below 120 °C for most
permanent gases), but more soluble in organic solvents.
Pressure
For condensed phases (solids and liquids), the pressure dependence of solubility is typically
weak and usually neglected in practice. The pressure dependence of solubility does occasionally
have practical significance. For example, precipitation fouling of oil fields and wells by calcium
sulfate (which decreases its solubility with decreasing pressure) can result in decreased
productivity with time.
Solubility of gases
Henry's law is used to quantify the solubility of gases in solvents. The solubility of a gas in a
solvent is directly proportional to the partial pressure of that gas above the solvent. The solubility
of gases is sometimes also quantified using Bunsen solubility coefficient.
In the presence of small bubbles, the solubility of the gas does not depend on the bubble radius in
any other way than through the effect of the radius on pressure (i.e. the solubility of gas in the
liquid in contact with small bubbles is increased due to pressure increase by Δp = 2γ/r;
see Young–Laplace equation).
Polarity
A popular aphorism used for predicting solubility is "like dissolves like" also expressed in
the Latin language as "Similia similibus solventur". This statement indicates that a solute will
dissolve best in a solvent that has a similar chemical structure to itself. This view is simplistic,
but it is a useful rule of thumb. The overall salvation capacity of a solvent depends primarily on
its polarity. For example, a very polar (hydrophilic) solute such as urea is very soluble in highly
polar water, less soluble in fairly polar methanol, and practically insoluble in non-polar solvents
such as benzene. In contrast, a non-polar or lipophilic solute such as naphthalene is insoluble in
water, fairly soluble in methanol, and highly soluble in non-polar benzene.
Rate of dissolution
Dissolution is not an instantaneous process. The rate of solubilization (in kg/s) is related to the
solubility product and the surface area of the material. The speed at which a solid dissolves may
depend on its crystalline or lack thereof in the case of amorphous solids and the surface area
(crystallite size) and the presence of polymorphism. Many practical systems illustrate this effect,
for example in designing methods for controlled drug delivery. In some cases, solubility
equilibrium can take a long time to establish (hours, days, months, or many years; depending on
the nature of the solute and other factors).

Applications

Solubility is of fundamental importance in a large number of scientific disciplines and practical

applications, ranging from ore processing and nuclear reprocessing to the use of medicines, and
the transport of pollutants.
Solubility is often said to be one of the "characteristic properties of a substance", which means
that solubility is commonly used to describe the substance, to indicate a substance's polarity, to
help to distinguish it from other substances, and as a guide to applications of the substance. For
example, indigo is described as "insoluble in water, alcohol, or ether but soluble in chloroform,
nitrobenzene, or concentrated sulfuric acid.
Solubility of a substance is useful when separating mixtures. For example, a mixture of salt
(sodium chloride) and silica may be separated by dissolving the salt in water, and filtering off the
undissolved silica. The synthesis of chemical compounds, by the milligram in a laboratory, or by
the ton in industry, both make use of the relative solubilities of the desired product, as well as
unreacted starting materials, byproducts, and side products to achieve separation.
Another example of this is the synthesis of benzoic acid from phenyl magnesium
bromide and dry ice. Benzoic acid is more soluble in an organic solvent such
as dichloromethane or diethyl ether, and when shaken with this organic solvent in a separatory
funnel, will preferentially dissolve in the organic layer. The other reaction products, including
the magnesium bromide, will remain in the aqueous layer, clearly showing that separation based
on solubility is achieved. This process, known as liquid–liquid extraction, is an important
technique in synthetic chemistry. Recycling is used to ensure maximum extraction.
Partition Coefficient
Partition coefficient (P) or distribution coefficient (D) is the ratio of concentrations of
a compound in a mixture of two immiscible solvents at equilibrium. This ratio is therefore a
comparison of the solubilities of the solute in these two liquids. The partition coefficient
generally refers to the concentration ratio of un-ionized species of compound, whereas the
distribution coefficient refers to the concentration ratio of all species of the compound (ionized
plus un-ionized).

Nomenclature

Partition coefficient and log P

The partition coefficient, abbreviated P, is defined as a particular ratio of the concentrations of
a solute between the two solvents (a biphase of liquid phases), specifically for un-ionized solutes,
and the logarithm of the ratio is thus log P. When one of the solvents is water and the other is
a non-polar solvent, then the log P value is a measure of lipophilicity or hydrophobicity. The
defined precedent is for the lipophilic and hydrophilic phase types to always be in
the numerator and denominator respectively; for example, in a biphasic system of n-
octanol (hereafter simply "octanol") and water.

Distribution coefficient and log D

The distribution coefficient, log D, is the ratio of the sum of the concentrations of all forms of the
compound (ionized plus un-ionized) in each of the two phases, one essentially always aqueous;
as such, it depends on the pH of the aqueous phase, and log D = log P for non-ionizable
compounds at any pH. For measurements of distribution coefficients, the pH of the aqueous
phase is buffered to a specific value such that the pH is not significantly perturbed by the
introduction of the compound. The value of each log D is then determined as the logarithm of a
ratio—of the sum of the experimentally measured concentrations of the solute's various forms in
one solvent, to the sum of such concentrations of its forms in the other solvent.

Application
Pharmacology
A drug's distribution coefficient strongly affects how easily the drug can reach its intended target
in the body, how strong an effect it will have once it reaches its target, and how long it will
remain in the body in an active form. Hence, the log P of a molecule is one criterion used in
decision-making by medicinal chemists in pre-clinical drug discovery, for example, in the
assessment of druglikeness of drug candidates.
Pharmacokinetics
In the context of pharmacokinetics (what the body does to a drug), the distribution coefficient
has a strong influence on ADME properties of the drug. Hence the hydrophobicity of a
compound (as measured by its distribution coefficient) is a major determinant of how drug-like it
is. More specifically, for a drug to be orally absorbed, it normally must first pass through lipid
bilayers in the intestinal epithelium (a process known as transcellular transport). For efficient
transport, the drug must be hydrophobic enough to partition into the lipid bilayer, but not so
hydrophobic, that once it is in the bilayer, it will not partition out again.
Pharmacodynamics
In the context of pharmacodynamics (what a drug does to the body), the hydrophobic effect is
the major driving force for the binding of drugs to their receptor targets. On the other hand,
hydrophobic drugs tend to be more toxic because they, in general, are retained longer, have a
wider distribution within the body (e.g., intracellular), are somewhat less selective in their
binding to proteins, and finally are often extensively metabolized. In some cases the metabolites
may be chemically reactive. Hence it is advisable to make the drug as hydrophilic as possible
while it still retains adequate binding affinity to the therapeutic protein target. For cases where a
drug reaches its target locations through passive mechanisms (i.e., diffusion through
membranes), the ideal distribution coefficient for the drug is typically intermediate in value
(neither too lipophilic, nor too hydrophilic); in cases where molecules reach their targets
otherwise, no such generalization applies.
Environmental science
The hydrophobicity of a compound can give scientists an indication of how easily a compound
might be taken up in groundwater to pollute waterways, and its toxicity to animals and aquatic
life. Partition coefficient can also be used to predict the mobility of radionuclides in
groundwater. In the field of hydrogeology, the octanol–water partition coefficient Kow is used to
predict and model the migration of dissolved hydrophobic organic compounds in soil and
groundwater.
Agrochemical research
Hydrophobic insecticides and herbicides tend to be more active. Hydrophobic agrochemicals in
general have longer half-lives and therefore display increased risk of adverse environmental
impact.
Metallurgy
In metallurgy, the partition coefficient is an important factor in determining how different
impurities are distributed between molten and solidified metal. It is a critical parameter for
purification using zone melting, and determines how effectively an impurity can be removed
using directional solidification, described by the Scheil equation.
Hydrogen bonding
A hydrogen bond (often informally abbreviated H-bond) is a partial intermolecular bonding
interaction between a lone pair on an electron rich donor atom, particularly the second-row
elements nitrogen (N), oxygen (O), or fluorine (F), and the antibonding orbital of a bond
between hydrogen (H) and a more electronegative atom or group. Such an interacting system is
generally denoted Dn–H···Ac, where the solid line denotes a polar covalent bond, and the dotted
or dashed line indicates the hydrogen bond. The use of three centered dots for the hydrogen bond
is specifically recommended by the IUPAC. While hydrogen bonding has both covalent and
electrostatic contributions, and the degrees to which they contribute are currently debated, the
present evidence strongly implies that the primary contribution is covalent.
Types of Hydrogen Bonding
There are two types of hydrogen bonding
1. Intermolecular Hydrogen Bonding: This occurs when the hydrogen bonding is
between H-atom of one molecule and an atom of the electronegative element of another
molecule. For example. (i) Hydrogen bond between the molecules of hydrogen fluoride.
(ii) Hydrogen bond in alcohol or water molecules.
2. Intramolecular hydrogen bonds are those which occur within one single molecule. This
occurs when two functional groups of a molecule can form hydrogen bonds with each
other.
Protein binding
Plasma protein binding refers to the degree to which medications attach to proteins within the
blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug
is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that
drugs bind to are human serum albumin, lipoprotein, glycoprotein, and α, β‚ and γ globulins.
Binding (Drug Distribution)
A drug in blood exists in two forms: bound and unbound. Depending on a specific drug's affinity
for plasma protein, a proportion of the drug may become bound to plasma proteins, with the
remainder being unbound. If the protein binding is reversible, then a chemical equilibrium will
exist between the bound and unbound states, such that:
Protein + drug ⇌ Protein-drug complex
Notably, it is the unbound fraction which exhibits pharmacologic effects. It is also the
fraction that may be metabolized and/or excreted. For example, the "fraction bound" of
the anticoagulant warfarin is 97%. This means that of the amount of warfarin in the blood,
97% is bound to plasma proteins. The remaining 3% (the fraction unbound) is the fraction
that is actually active and may be excreted.
Protein binding can influence the drug's biological half-life. The bound portion may act as a
reservoir or depot from which the drug is slowly released as the unbound form. Since the
unbound form is being metabolized and/or excreted from the body, the bound fraction will
be released in order to maintain equilibrium.
Since albumin is alkalotic, acidic and neutral drugs will primarily bind to albumin. If
albumin becomes saturated, then these drugs will bind to lipoprotein. Basic drugs will bind
to the acidic alpha-1 acid glycoprotein. This is significant because various medical
conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoproteins.
Chelation
Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or
presence of two or more separate coordinate bonds between a polydentate (multiple
bonded) ligand and a single central atom. These ligands are called chelants, chelators, chelating
agents, or sequestering agents. They are usually organic compounds. Chelation is useful in
applications such as providing nutritional supplements, in Chelation therapy to remove toxic
metals from the body, as contrast agents in MRI scanning, in manufacturing using homogeneous
catalysts, in chemical water treatment to assist in the removal of metals, and in fertilizers.
Bioisosterism
In medicinal chemistry, Bioisosterism are chemical substituents or groups with similar physical
or chemical properties which produce broadly similar biological properties to another chemical
compound. In drug design, the purpose of exchanging one Bioisosterism for another is to
enhance the desired biological or physical properties of a compound without making significant
changes in chemical structure. The main use of this term and its techniques are related to
pharmaceutical sciences. Bioisosterism is used to reduce toxicity, change bioavailability, or
modify the activity of the lead compound, and may alter the metabolism of the lead.

Classical Bioisosterism

Classical Bioisosterism was originally formulated by James Moir and refined by Irving
Langmuir as a response to the observation that different atoms with the same valence
electron structure had similar biological properties.
For example, the replacement of a hydrogen atom with a fluorine atom at a site of metabolic
oxidation in a drug candidate may prevent such metabolism from taking place. Because the
fluorine atom is similar in size to the hydrogen atom the overall topology of the molecule is not
significantly affected, leaving the desired biological activity unaffected. However, with a
blocked pathway for metabolism, the drug candidate may have a longer half-life.

• Procainamide, an amide, has a longer duration of action than Procaine, an ester, because of
the isosteric replacement of the ester oxygen with a nitrogen atom. Procainamide is a
 classical Bioisosterism because the valence electron structure of a disubstituted oxygen atom
is the same as a trisubstituted nitrogen atom, as Langmuir showed.

Non-classical Bioisosterism

Non-classical Bioisosterism may differ in a multitude of ways from classical Bioisosterism, but
retain the focus on providing similar steric and electronic profile to the original functional group.
Whereas classical Bioisosterism commonly conserve much of the same structural properties,
nonclassical Bioisosterism are much more dependent on the specific binding needs of the ligand
in question and may substitute a linear functional group for a cyclic moiety, an alkyl group for a
complex heteroatom moiety, or other changes that go far beyond a simple atom-for-atom switch.
For example, a chlorine -Cl group may often be replaced by a trifluoromethyl -CF3 group, or by
a cyano -C≡N group, but depending on the particular molecule used the substitution may result
in little change in activity, or either increase or decrease affinity or efficacy depending on what
factors are important for ligand binding to the target protein. Another example is aromatic rings,
a phenyl -C6H5 ring can often be replaced by a different aromatic ring such
as thiophene or naphthalene which may improve efficacy, change specificity of binding, or
reduce metabolically labile sites on the molecule, resulting in better pharmacokinetic properties.
Optical isomerism

Optical isomers are two compounds which contain the same number and kinds of atoms, and
bonds (i.e., the connectivity between atoms is the same), and different spatial arrangements of
the atoms, but which have non-super imposable mirror images. Each non-super imposable mirror
image structure is called an enatiomer.

Geometrical Isomerism
Geometric isomers are chemical species with the same type and quantity of atoms as another
species, yet having a different geometric structure. Atoms or groups exhibit different spatial
arrangements on either side of a chemical bond or ring structure.
Learning Outcomes
➢ Understand the Introduction, History ,Physicochemical properties & Drug
metabolism of Medicinal chemistry.